This application addresses the program announcement for Mechanisms Mediating Osteoarthritis in Aging PA-12-018. Our focus is on understanding the role of mechanobiological factors in the onset and progression of osteoarthritis in a mouse model with compromised tissue properties. Osteoarthritis (OA) reduces mobility and function by altering the structure and property of the affected joint, particularly of the cartilage and bone. Both biological and mechanical factors have been linked to the development and onset of OA, including mechanical loading. We have developed non-invasive in vivo mouse loading model of the mouse knee that recapitulates clinical OA-like features temporally and anatomically. Combining this model with transgenic mice, we plan to investigate the role of altered cartilage composition in the development of OA using transgenic mice that spontaneously develop early OA-like features at 3 months of age. We hypothesize that controlled mechanical loading of the knee joints in mice with abnormal cartilage matrix composition and properties will result in enhanced OA-like changes in articular cartilage and peri-articular bone compared to their wild type littermates. To determine whether loading expedites the development of OA-like changes, we will compare mice with type XI haploinsufficiency (cho/+ mice) to wild-type controls at 3 and 6 months of age and apply 1, 2 and 6 weeks of loading. Changes in cartilage, bone and joint mobility will be assessed by histology, microcomputed tomography, immunohistochemistry, RT-qPCR, atomic force microscopy, and kinematic analysis. This loading model provides an opportunity to study the response to mechanical stimuli without concurrent joint trauma to better understand mechanical factors contributing to OA and the interaction of biological and mechanical factors in joint degeneration.